Huntington's disease (HD), an inherited neurodegenerative disorder that affects the lives of more than 100,000 people in the US, is caused by an unstable CAG repeat in the 4p16.3 HD gene that encodes a variable polyglutamine tract in huntingtin. This grant continues to have the goal of using targeted mutations in the mouse's HD gene homolog (Hdh) to delineate this intriguing disease-initiating mechanism and its earliest consequences in striatum, to provide assays for identifying factors that modify the earliest steps in the disease process. Our studies comprise three new Aims. In exploring huntingtin function in the HD-trigger mechanism we have found that huntingtin may associate with and regulate the function and histone 3 methyltransferase activity of Eed polycomb repressive complex (PRC2/3). Aim 1 will test this hypothesis and determine whether the effects of lengthening the polyglutamine tract in huntingtin may implicate huntingtin activity in the HD trigger mechanism. Aim 2 will identify the transcriptional regulators of the immediate early gene response in striatum to the HD CAG repeat that causes the majority of HD cases, including Nrf1/E2F senescence target genes. To identify factors that make striatal neurons so vulnerable to the effects of the HD-trigger, Aim 3 will test the hypothesis that conditional expression of mutant huntingtin only in medium sized spiny striatal neurons will be sufficient to elicit the early disease cascade, indicating that the processes that modify the disease process are intrinsic to these cells. These studies will yield valuable information and assays for identifying genes and compounds that may interfere with the HD-trigger mechanism and its early effects in the striatal neurons that are the weakest link in HD patients.